A growing body of evidence indicates that the enzyme DNA topoisomerase II is an important target for the anti-tumor effect of a diverse group of drugs including intercalating agents and epipodophyllotoxins. The important properties common to all these agents which allow them to interact with the enzyme are unknown. Based on the fact that the known active agents are structurally diverse, possess important clinical anti-tumor activity and share a common intracellular target, we believe it is highly likely that other compounds exist which, by virtue of their interaction with topoisomerase, will exhibit useful anti-tumor activity. Thus, the goals of our program are (1) to elucidate the nature of the physical interaction of topoisomerase II with specific, active anti-tumor agents; (2) to explore the potential of DNA topoisomerase I as a therapeutic target; (3) to design new agents directed at topoisomerase I and II; (4) to develop sensitive, efficient assays for screening new compounds for activity against topoisomerases I and II and (5) to characterize topoisomerases in vivo in ways which will elucidate the biological bases for therapeutic success or failure.